Variation in osteoarthritis biomarker serum comp levels in Mexican Americans is associated with SNPs in a region of chromosome 22q encompassing MICAL3, BCL2L13, and BID

Abstract

Acetylated-Histone 3 (A-H3) level was increased upon treatment with all 4 HDIs, consistent with effective suppression of HDAC activity. The most effective specific HDI was MS275, which showed similar A-H3 levels to TSA, but exhibited some undesirable effects of pan-HDI. PCI increased A-H3 levels, though not as effective as MS275, but also reduced the negative effects of TSA, such as decreased COX-2 and MMP-3 expression under treatment with IL1b. Also, the additive effect of TSA and IL1b on the secretion of MMP3 was not observed in the case of PCI. Chondrocyte proliferation and survival was unaffected by the tested HDIs after 24 h of culture, with the exception of Droxinostat at concentration over 20 mm(decreased proliferation as shown by MTS assay and increased cell death as shown by Live/Dead assay). However, upon longer incubation (48 h), both TSA (200 nM) and Droxinostat reduced chondrocyte proliferation, while MS275, PCI and Tubostatin A increased it. Conclusions: The HDI, PCI, appears to be a promising candidate for reducing inflammatory and catabolic markers in chondrocytes exposed to pro-inflammatory cytokines. Further studies will investigate the effect of increasing PCI concentrations in two in vitro chondrocytebased OA models: (1) IL1b treatment; and (2) exposure to supraphysiological mechanical loading. In addition, MS275 could be a good alternative to pan-HDAC inhibitors, such as TSA, when longer exposure times are needed.

RNA-binding proteins potentially regulate the alternative splicing of apoptotic genes during knee osteoarthritis progression

“…Apoptosis-induced morphological changes have been observed in the chondrocytes in degenerative cartilage, suggesting a pathway for OA pathology [ 35 ]. Our findings are consistent with those of another study that revealed that BCL2L13, a proapoptotic member of the BCL-2 family of apoptosis protein, plays a role in the mitochondrial apoptosis pathway, which is altered in OA [ 36 ]. By upregulating BCL2L13 expression, the long noncoding RNA SNHG15 can inhibit OA progression [ 37 ].…”

Population history and gene divergence in Native Mexicans inferred from 76 human exomes

“…Of notice, two apoptosis-related genes were identified this way in TAR, BCL2L13 (BCL2 like 13), and ATRAID (All-Trans Retinoic Acid-Induced Differentiation Factor). The former encodes for a pro-apoptotic protein that localizes in the mitochondria and is highly expressed in skeletal muscle (GTEx release V7) and is found in a locus previously associated to osteoarthritis (OA) risk in Mexican Americans (Coan et al 2013). ATRAID (alternative name APR-3, apoptosis-related protein 3), is thought to be involved in apoptosis hematopoietic development and differentiation, and in positive regulation of bone mineralization and osteoblast differentiation (Zou et al 2011).…”